This invention relates to a method for the syntheses of chiral pyrrolidines and piperidines by the intramolecular ring closure of anomeric mixtures of 4-amino-and 5-amino-2-trifluoromethanesulfonates of methyl furanosides. More particularly, the invention relates to the efficient syntheses from diacetone glucose of 1,4-dideoxy-1,4-imino-D-arabinitol -known as DAB1- (1), (2S,3R,4R)-3,4-dihydroxyproline (2), fagomine [1,5-imino-1,2,5-trideoxy-D-arabino-hexitol](3), and (2S,3R,4R)-3,4-dihydroxypipecolic acid (4) by intramolecular nucleophilic displacement by an amino function of 2-O-trifluoromethanesulphonates of anomeric mixtures of methyl furanosides. All four of these compounds previously have been screened as potential inhibitors of HIV replication [Tyms et al., Lancet, pp. 1025-1026 (1987); Fleet et al., FEBS Lett. 237, 128-132 (1988)]as part of a project investigating the potential of amino sugar derivatives in dissecting glycoprotein biosynthesis. 1,4-dideoxy-1,4-imino-L-arabinitol, LAB1, the enantiomer of (1), is a powerful inhibitor of cytopathic effect of HIV at concentrations which were not cytotoxic. ##STR1##
Naturally occurring and synthetic polyhydroxylated pyrrolidines and piperidines constitute a powerful class of glycosidase inhibitors. See, respectively, Fellows and Fleet, Alkaloidal Glycosidase Inhibitors from Plants, Chap. 13 in Natural Product Isolation, (ed. G. H. Wagman and R. Cooper), p. 540-560, Elsevier, (1988), and Fleet, Amino Sugar Derivatives and Related Compounds as Glycosidase Inhibitors Topics in Medicinal Chemistry, 4th SCI-RSC Med. Chem. Symp. Cambridge, Sept. 1987, (Ed. P. R. Leeming), p. 149-162, Royal Society of Chemistry, London, (1988). Both the natural product DAB1 (1), isolated from Anglyocalyx boutiqueanus [Nash et al., Phytochemistry, 24, 1620 (1985); Jones et al., Tetrahedron Lett. 26, 3127 (1985)]and Arachniodes standishii, [Furukawa et al., Phytochemistry 24, 593 (1985)]and its enantiomer LAB1 are powerful inhibitors of a range of .alpha.-glucosidases [Fleet et al., Tetrahedron Lett. 26, 3127 (1985); Scofield et al., Life Sci. 39, 645 (1986)].
DAB1 (1) has been synthesized previously from D-xylose [Fleet et al., Tetrahedron Lett. 26, 3127-3130 (1985); Fleet and Smith, Tetrahedron42, 5685-5692 (1986)]and from (S)-glutamic acid [Ikota and Hanaki Chem. Pharm. Bull., 35, 2140 (1987)]; LAB1has been prepared from D-xylose [Fleet et al., Tetrahedron, 42, 5685-5692 (1986); Naleway et al., Carbohydr. Res., 179, 199 (1988)]and L-arabinose [Jones, supra.].
The structurally related fungal metabolite FR 900483, an anhydro form of 4-amino-4-deoxy-D-arabinose, has been shown to be an immunomodulator [Kayakira et al., Tetrahedron Lett. 29, 1725 (1988) and Shibata et al., J. Antibiot., 41, 296 (1988)]; other hydroxylated pyrrolidines also may have promise as immunoregulator agents [Ikota and Hanaki, Chem. Pharm. Bull., 36, 1143 (1988)].
Fagomine (3) isolated from Fagopyrum esculentum [Koyama and Sakamura, Agric. Biol. Chem., 38, 1111 (1974); Koyama et al., Agric. Biol. Chem., 38, 1467 (1974)]and as the 4-O-.beta.-glucoside from Xanthocercis zambesiaca [Evans et al., Tetrahedron Lett., 26, 1465 (1985)], is a moderate inhibitor of isomaltase [Scofield, supra.]. Fagomine has previously been prepared from glucose [Fleet et al., Tetrahedron, 43, 979-990 (1987)].
Both DAB1 (1) and fagomine have also been prepared by sequences involving aldolases [Ziegler et al., Angew. Chem. Int. Ed. Engl., 27, 716 (1988); Pederson and Wong, Heterocycles, 28, 477 (1989); and von der Osten et al., J. Am. Chem. Soc. 111, 3924-3927 (1989)]. ##STR2##
There is considerable interest in the synthesis of optically pure .beta.- and .gamma.-hydroxy-.alpha.-amino acids. Although a few good non-enzymic methods for their asymmetric synthesis have been devised [Jung and Jung, Tetrahedron Lett., 30, 6637 (1989) and references cited therein], carbohydrates have long been established as homochiral starting meterials for the synthesis of non-protein amino acids [Hanessian, Total Synthesis of Natural Products: The Chiron Approach, Pergamon, Oxford, 1983; Shenbagamurthi et al., J. Med. Chem. 29, 802 (1986) and references cited therein]. The value of simply protected sugar lactones--in which azide is easily introduced at the carbon .alpha. to the lactone carbonyl--in short and efficient syntheses of highly functionalized amino acids such as hydroxylated prolines and pipecolic acids has been recognized. Thus, introduction of an azide function with retention of configuration at C-2 of D-ribonolactone [Dho et al., Tetrahedron Lett., 27, 3203 to 3204 to 3208 (1986)] provides a powerful intermediate for the synthesis of homochiral D-amino acids such as 2R,3 S,4R-dihydroxyproline [Baird et al., J. Chem. Soc. Perkin Trans. 1, 1785 (1987)]. Introduction of azide .alpha. to the carbonyl group of glucuronolactone [Bashyal et al., Tetrahedron Lett., 27, 3205 (1986)] allowed short syntheses of the D-amino acids 2R,3R,4R-dihydroxyproline and 2R,3R,4R,5S-trihydroxypipecolic acids and of the L-amino acids 2S,3R,4R,5S-trihydroxypipecolic acid (BR1), 2S,4S,5S-dihydroxypipecolic acid and bulgecinine [Bashyal et al., Tetrahedron 43, 415-422 (1987); Bashyal et al., Tetrahedron, 43, 423 to 430 (1987)]. More lengthy syntheses derived by introduction of nitrogen at C-2 of glucose have been reported for the synthesis of 2S,3R,4R,5R-trihydroxypipecolic acid [Fleet et al., Tetrahedron, 43, 979-990 (1987)], BR1 [Bernotas and Ganem, Tetrahedron Lett., 26 4981 (1985)] and bulgecinine [Wakamiya et al., Tetrahedron Lett., 26 4759 (1985)]. 2S,3S,4R-Dihydroxyproline has been prepared by initial introduction of nitrogen at C-3 of glucose [Fleet et al., Tetrahedron, 43, 3095-3108 (1987)]; a similar approach has been used for the synthesis of other .beta.-hydroxy-.alpha.-amino acids [Rao et al., Tetrahedron Lett., 30, 6769 (1989)].